The candidate for this RSDA application, Dr. Rueben Gonzales, obtained his Ph.D. in Pharmacology from the Univ. of Texas in 1983. After performing post-doctoral work for 3 years, Dr. Gonzales began to establish an independent research career as an academic scientist with a position at LSU Medical Center (2 yr) and currently is an Assistant Professor at the Univ. of Texas. The candidate has been productive in the alcohol field as evidenced by 36 publications and by obtaining 4 competitive extramural research grants. Dr. Gonzales' immediate goals are to firmly establish himself as an independent researcher in the alcohol field. Long term goals include continuing to contribute to knowledge of the basic biochemical mechanisms of ethanol's effects on brain function as an academic scientist, along with training pre- and post-doctoral students for careers in alcohol related research and helping with administrative duties of the University as a faculty member. The College of Pharmacy will support the research career development of the candidate by providing laboratory space and equipment and by relieving the candidate of a large teaching load during the period of the RSDA. The Dept. of Pharmacology is an excellent atmosphere for fostering the scientific growth and development of the candidate because of the possibility of collaboration with several notable senior faculty with strong research programs and with other neuroscientists through the Institute for Neuroscience. The RSDA will significantly enhance the candidate's research career development by allowing more time for research. The research project involves the investigation of the acute and chronic effects of ethanol on N-methyl-D-aspartate (NMDA) mediated responses. The NMDA receptor, a subtype of excitatory amino acid receptor, is implicated in learning, memory, and neurodegenerative processes. Preliminary data suggest that ethanol, at concentrations which are consistent with its pharmacological range achieved in vivo (10-60 mM), inhibits NMDA receptor function. The major aim of this proposal is to define the site and mechanism of ethanol's inhibitory effect on NMDA receptor function at the molecular level. Functional assays (NMDA-stimulated transmitter release and modulation of phosphoinositide hydrolysis in rat brain slices, and in vivo microdialysis), along with radioligand binding techniques, will establish whether ethanol is acting at one or more of the proposed sites which modulate NMDA receptor function (glycine, polyamine, zinc). The knowledge gained from these studies will contribute to our understanding of the molecular mechanisms of an important receptor system in the brain at a basic level. In addition, information will also be gained about the possible role of this system in ethanol-induced neuronal adaptation or damage and may lead to new therapeutic approaches for the treatment of alcohol related problems.